Sensory experience influences brain development by activating neural circuits. The activation of these pathways leads to calcium-dependent regulation of various aspects of neuronal function such as synaptic plasticity, cell survival, and axonal and dendritic remodeling. In most of these instances calcium signals exert long-lasting cellular effects by activating transcription factors that induce expression of target genes. Our overall goal is to gain insight into the mechanisms by which calcium signals influence brain development via transcriptional activation. One of the major effects of calcium signaling in neurons is to regulate changes in synaptic strength. At many synapses, the direction and extent of change in synaptic strength depends on the stimulus parameters. For example, at the CA3-CA1 Schaffer collateral synapse in the hippocampus, low frequency stimulation leads to long term depression (LTD) and high frequency stimulation leads to long term potentiation (LTP). The ability of a synapse to undergo plasticity can itself be modified by various manipulations, and the resulting shift in the plasticity state of the cell is often referred to as metaplasticity. We propose to explore the hypothesis that metaplasticity at the CA3- CA1 synapse is regulated by CREST-mediated transcription. The goals of the project are: (i) To examine the role of CREST in activity-dependent down-regulation of GluR2 expression;(ii) To examine the role CREST in activity-dependent regulation of NR2B expression;(iii) To examine the role of CREST in regulating the AMPA: NMDA ratio in vivo and to determine if CREST regulates the fraction of silent synapses;and (iv) To determine if CREST regulates LTP in hippocampal CA3-CA1 synapses and whether loss of CREST compromises metaplasticity.

Public Health Relevance

The goal of this project is to understand the role of a nuclear factor called CREST in the development and reorganization of hippocampal connections. Several developmental neurological disorders, such as Autism and Rett syndrome, are characterized by defects in neuronal connectivity, but the cellular and molecular basis of these disorders is not well-understood. We have recently found that CREST regulates the expression of several genes, including MeCP2, a gene that is mutated in Rett Syndrome. We will examine how CREST regulates MeCP2 expression and how that affects the ability of the brain to respond to synaptic inputs. The findings of this project should guide efforts to better understand and develop therapeutic strategies for childhood neurological disorders.